Exposing rats to complex, stimulating, and social housing (i.e., enriched environment; EE) improves cognitive and motor performance after traumatic brain injury (TBI). The specific mechanisms that underlie this effect are unknown, although there is evidence suggesting that EE enhances cortical plasticity. Furthermore, subcortical cholinergic afferents are critically involved in eliciting specific forms of plasticity in rats, such as estrogen-mediated plasticity in the hippocampus, denervation-mediated plasticity in the frontal cortex, and experience-related plasticity in both visual and auditory cortices. The proposed studies will test the hypothesis that cholinergic neurons are important mediators of EE-induced change after TBI and that there are gender differences in this mediation. As such, cholinergic enhancement may be an effective means of augmenting the beneficial effects of `ancillary' treatments, such as behavioral enrichment (i.e., rehabilitation), in patients with TBI. Five specific aims are proposed to test the overall hypothesis. Aim 1 will determine whether disrupting basal forebrain cholinergic neurons (BFCNs) blunts the ability of EE to improve behavioral performance after TBI produced with the well-established controlled cortical impact injury model in conjunction with saporin (SAP)-lesions. Aim 2 will determine to what extent EE-induced synaptic plasticity in these same animals (i.e., Aim 1) is altered and if plasticity correlates with performance. Because hormones are known to modulate cholinergic function and males and females respond differently to EE after TBI, Aim 3 will assess cortical plasticity and functional improvement with EE in gonadally intact vs. ovariectomized (OVX) female rats after TBI+/-SAP lesions and compare the results to males from Aims 1-2. Aim 4 will assess the effect of a delayed and chronic treatment regimen (1-20 days post-injury) with the FDA-approved acetylcholinesterase inhibitor donepezil in male and both intact and OVX female rats after TBI to determine if motor and acquisition of spatial learning and memory can be facilitated in either group via an additive or synergistic effect of donepezil+EE. Lastly, Aim 5 will expand on the rehabilitative strategy of Aim 4 by determining whether the effects of donepezil+EE are sustained after the subjects are returned to standard living conditions with and without continued pharmacotherapy. Our long-term goal is to develop therapies that facilitate functional recovery after human TBI. PUBLIC HEALTH RELEVANCE: Traumatic brain injury is a significant health care issue affecting millions of individuals each year in the US alone. Patients are often left with long lasting physical and cognitive disabilities for which there are no accepted treatments. Pharmacotherapies affecting the cholinergic system have been shown to provide some benefit, as has environmental enrichment. The studies in this proposal seek to evaluate the effects of donepezil and enrichment and their effect on functional outcome after TBI. The study further seeks to test the hypothesis that cholinergic neurons are important mediators of behaviorally induced change after TBI and that there are sex differences in this mediation. The outcome has the potential to provide a novel treatment strategy for rehabilitation of TBI patients.